Transcranial magnetic stimulation

Juan J López-Ibora,b, Marı́a-Inés López-Ibora and José I Pastranac

a
b
Department of Psychiatry, Complutense University, Purpose of review
Psychiatry and Mental Health Institute, San Carlos
University Hospital and cClı́nica López-Ibor, Madrid,
To present state-of-the-art transcranial magnetic stimulation (TMS) therapy, especially
Spain when it is used in psychiatric disorders, on the basis of an exhaustive literature
Correspondence to Juan J. López-Ibor Jr., search from 2006 to date (June 2008) on TMS papers published in Medline and
Doctor Juan José López Ibor 2, 28035 Madrid, Spain Embase. Other references and comments from our own experience started 8 years
Tel: +34 913 73 91 19; fax: +34 913 16 27 40;
e-mail: jli@lopez-ibor.com ago have also been taken into account.
Recent findings
Current Opinion in Psychiatry 2008, 21:640–644
The mechanism of action of TMS is now better understood. There is strong evidence of
the safety and tolerability of TMS when standard protocols are used. The efficacy
of the stimulation of the dorsolateral prefrontal cortex in depression is well documented,
and there is evidence of the utility of TMS in posttraumatic stress disorder, in
persistent auditory hallucinations in schizophrenia and in attention-deficit disorder
with hyperactivity.
Summary
There is enough evidence of the efficacy and safety of TMS in depression to include
this technique in the therapeutic protocols of major depression. However, more
research is needed on the use of this technique in other psychiatric and nonpsychiatric
disorders such as posttraumatic stress disorder, persistent auditory hallucinations,
attention-deficit disorder with hyperactivity and tinnitus.

Keywords
attention-deficit disorder with hyperactivity, auditory hallucinations, dorsolateral
prefrontal cortex, posttraumatic stress disorder, repeated transcranial magnetic
stimulation, transcranial magnetic stimulation, treatment-resistant depression

Curr Opin Psychiatry 21:640–644

ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7367

or pain [4]. This high tolerability, along with the possible

Introduction indications, facilitates its applicability.
Transcranial magnetic stimulation (TMS) is only two
decades old. Originally it was introduced to investigate The exact mechanism of action of TMS is still unknown.
in a noninvasive way nervous propagation along the A recent study on cat visual cortex has shown that pulse
corticospinal tract, spinal roots and peripheral nerves in trains of rTMS provoke a dose-dependent response,
humans. Repeated transcranial magnetic stimulation which is enhanced either with the duration or the inten-
(rTMS) was initially used as a therapeutic method in sity of stimulation [5]. Short TMS pulse trains elicited an
neuropsychiatry illnesses with abnormalities of neuronal initial activation (approximately 1 min) and a prolonged
excitability [1]. Comprehensive and detailed information suppression (5–10 min) of neural responses. Further-
about the method appears in George and Belmaker’s more, TMS disrupted the temporal structure of activity
book [2]. In 2007, TMS was approved for treatment- by altering phase relationships between neural signals.
resistant depression in Canada, Australia, New Zealand,
the European Union and Israel, whereas it is still in phase Neural activity changes were also reflected in haemody-
IV studies in the United States [3]. The remaining uses namic signals; TMS led to an initial increase and sub-
are still experimental. sequent longer lasting decrease in tissue oxygenation
and haemoglobin concentration [6]. In principle,
TMS is safe and well tolerated with minimal side effects dose-dependent linearity on this effect is confirmed in
reported. Up to now there is no evidence of either death previous studies that obtained an increase in excitability
or epileptic seizures in published studies including over in the dorsolateral prefrontal cortex (DLPFC) with high
10 000 treatment sessions. TMS is well tolerated with a frequencies and transitory cortical inhibition with low
low dropout rate for adverse events (4.5%) that were frequencies [7]. On the contrary, there is evidence that
generally mild and limited to transient scalp discomfort rTMS has an effect on the metabolism of tryptophan and
0951-7367 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/YCO.0b013e3283136a0c

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Transcranial magnetic stimulation López-Ibor et al. 641

serotonin in limbic areas [8], whereas the application of

acute TMS lacks the normalizing effect of brain-derived Transcranial magnetic stimulation in
neurotrophic factor (BDNF) that takes place with rTMS depression
[9]. TMS in psychiatry has been more widely used and
investigated in depression. TMS has also been able to
One of the major theoretical and practical aspects is the identify an asymmetry of the functioning of the brain
position of the coil. There are several standardized options hemispheres in depressive disorders. The reasons why in
for the manual placement of the coil, and an optically major depression (MDD) the right DLPFC (RDLPFC)
tracked frameless stereotaxic navigation procedure, similar is hyperactive and the left (LDLPFC) is hypoactive
to the one used in neurosurgery, is also available. Potential remain poorly understood. Nevertheless, with fMRI,
sources of imprecision are due to the fixation of a reference the hyperactivity of the RDLPFC correlates with the
frame to the patient’s head and the referencing procedure severity of the depression, which is also related to atten-
according to certain landmarks. The accuracy in 1728 tion modulation. The hypoactivity of the LDLPFC is
different sessions in nine patients (192 measurements related to the presence of negative emotions [16].
for one patient) with the stereotaxic system of positioning
All these aspects are very important in choosing the right
the coil has a mean deviation of only 2.5 mm. This high
technique for stimulation. In resistant depression, high-
resproducibility makes the procedure very adequate for
frequency rTMS (HFR-TMS) of the LDLPFC increases
rTMS treatments [10]. Other systems for placing the coil
the activation of the left precuneus, whereas low-
are the standard navigation systems, which reduce the
frequency rTMS (LFR-TMS) of the RDLPFC decreases
errors due to the anatomical variability between individ-
activity in the middle frontal gyrus. This reduction in the
uals. In one case the anatomical approach was used during
frontal activity does not seem to be unspecific, which is
the first week and led to clinical improvement. But in the
different from the HFR-TMS [17]. On the contrary, rTMS
second week there was greater improvement using the
of the LDLPFC in healthy volunteers affects the modu-
navigation system. Via MRI reconstruction it transpired
lation of regions involved in tryptophan and serotonin
that the place initially stimulated was the Broca’s area, and
metabolism, in particular the left parahippocampal gyrus
the DLPFC was not 5 cm from the primary motor cortex
(BA 28), the right insula (BA 13), the right cingulate gyrus
of the hand but 8.3 cm. With the improvement in local-
(BA 31) and the cuneus (BA 18) [8]. rTMS of the LDLPFC
ization, the efficacy of the treatment was also improved
is able to normalize serum concentrations of BDNF, which
when compared with the first week’s results [11]. The
is often reduced in patients with major depression, in spite
navigation systems allow more precision in the localization
of the fact that acute TMS in healthy volunteers does not
of the area to be stimulated than the standard visual
alter the levels of BDNF [9].
anatomical system. Nevertheless, a recent study shows
that the positioning of the coil by means of a statistical rTMS of 10 Hertz (Hz) on the LDLPFC has a higher
visual approach is very consistent with the location by efficacy than sham rTMS [18]. rTMS exerts antidepress-
means of functional MRI (fMRI) [12]. In summary, ant effects either by enhancing left DLPFC excitability
although a maximum accuracy is desirable in the identi- with 10 Hz rTMS or by decreasing right DLPFC excit-
fication of the area to be stimulated, the classic visual ability with 1 Hz rTMS [19]. The different mechanism
anatomical systems are still a trustworthy method. of action for the high (increased excitability) and low
(transitory inhibition or dysfacilitation) frequencies has
It is not possible to predict the position and the neuronal been described previously by Pascual-Leone et al. [7].
population to be stimulated by TMS in atrophic brains
[13]. TMS in brains with atrophy requires the target to be Several controlled and open studies have shown high
identified on a case-by-case basis. Factors such as the levels of safety for rTMS [4,20]. Treatment discontinu-
distance between the scalp and the cortex must be taken ation because of side effects is only 4.5%. There have
into consideration when estimating the attenuation of the been no deaths or epileptic seizures reported in more
density of the flow. than 10 000 treatment sessions in published studies. The
side effects are minimal and well tolerated, consisting
Most of the clinical trials with TMS use a sham TMS as principally of migraines and minor skin injuries in the
control, although patients seem to be able to determine application area. There are no verified auditory or cog-
differences in their sensations and in the noise and heat nitive deficits after rTMS.
generated. Therefore, methods have been developed to
reproduce the subjective sensations in sham rTMS, both This safety allows an extension of treatment in resistant
in fixed as well as in mobile equipment [14]. A step depression, suggesting that longer courses of treatment
further that will also blind the researcher is a coil that may have additional therapeutic benefit, that is, 10 Hz
electronically shifts from the standard to the simulated rTMS on LDLPFC. In a randomized study comparing
application [15]. active and sham rTMS in patients with treatment-resistant

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 642 Clinical therapeutics

major depression who failed to respond to a 4-week treat- What seems to be more interesting is that rTMS seems to
ment period, 26% showed a good response and 11% full be an effective intervention for auditory hallucinations in
remission after a 6-week treatment period [21]. schizophrenia. A meta-analysis including 10 studies and
212 patients concluded that 1 Hz rTMS of the tempor-
The safety of the treatment encourages its application in oparietal cortex has an influence on the neurobiology of
neurological illnesses with depressive comorbidity that auditory hallucinations without having an effect on the
may deteriorate with the use of antidepressants and even general psychotic symptoms [32]. The treatments for
more with electroconvulsive treatment (ECT). rTMS of auditory hallucinations in schizophrenia have been pro-
10 Hz of the LDLPFC has been useful in the treatment vided for only short periods of time, although in two cases
of Parkinson’s disease, not only for depressive symptoms of relapse the treatment was successfully reused [33], but
but also for anxiety and motor symptoms, especially this was not the case in another publication [34].
during the ‘off’ moments [22].

rTMS has also been used as an augmentation strategy in Transcranial magnetic stimulation in other
resistant depression. Good results have been published in psychiatric disorders
a real vs. sham 10 Hz rTMS of the LDLPFC in a Efficacy of rTMS of the RDLPFC in posttraumatic stress
randomized study when 20 mg/day of escitalopram was disorder (PTSD) has been reported [35]. A combination
added in patients with severe depression who failed to of 1 Hz rTMS and exposure therapy [36] is also useful,
respond to two previous nontricyclic antidepressant treat- especially for hyperarousal symptoms. TMS application
ments [23]. Such results are similar to those with other can be of interest along with augmentation of exposure
pharmacological augmentation strategies, and, therefore, with drugs such as propranolol [37].
rTMS must be considered as one of the therapeutic
protocols prior to electroconvulsive therapy [24]. In obsessive–compulsive disorder (OCD), the results are
contradictory. Two double-blind placebo-controlled stu-
For the moment, no strong predictors of good response dies comparing rTMS and sham rTMS have shown that
have been identified [25], probably because of the TMS is ineffective in OCD, with one of the studies using
heterogeneity of the samples and the design and sample rTMS in combination with selective serotonin reuptake
size of the studies [26]. Nevertheless, in a revision of inhibitors (SSRI) [38,39]. The problem here is in identi-
rTMS of LDLPFC [27], it seemed that younger age and fying the target and the strategy (10 Hz stimulation vs.
less resistance to treatments were better predictors of a 1 Hz inhibition). The other problem may be the hetero-
good response. geneity of the samples.

In adults with attention-deficit disorder with hyperactiv-

Transcranial magnetic stimulation in ity (ADDH), double-pulse TMS detects a decrease in the
schizophrenia inhibitory motor region similar to that found in children
A reduced cortical inhibition has been described as a with ADDH [40]. TMS may be used as a diagnostic tool
characteristic of schizophrenia [2], which has been to establish disturbed impulsivity and hyperactivity on a
attributed to a GABAergic deficit [28]. Furthermore, neurophysiological level.
connectivity abnormalities between modules for motor
control, sensory–motor synchronization, temporary per-
ception and conscience of the action are present in Transcranial magnetic stimulation for
schizophrenia and could be, at least theoretically, inter- nonpsychiatric uses
rupted by rTMS [29]. In addition to the psychiatric uses previously mentioned,
TMS can be used in other applications of neuroscience.
On the contrary, deficits in backward masking (the per-
ception of a briefly displayed visual stimulus target is Neurology and neurophysiology of the continuum
impaired when followed by another visual stimulus task between child and adult attention-deficit disorder with
presented in the same location) have been reported in hyperactivity
schizophrenia. TMS has been used to identify a subgroup TMS has been used to measure changes in cortical
of patients having impaired evaluation of visual stimuli. excitability induced by drugs [41]. TMS may have a
TMS data also suggest that this deficit may not be place in the study of epilepsy and possibly in the treat-
localized to the occipital cortex [30]. Negative symptoms ment of some confirmed types. We have already
do not seem to respond to bilateral prefrontal cortex mentioned the therapeutic possibilities in movement
(PFC) rTMS, and only a slight improvement in autistic disorders [2]. Furthermore, TMS can facilitate the
symptoms was found after 3 weeks of TMS treatment study of spastic diplegia in children by detecting altera-
sessions [31]. tions in cortical inhibitory functions [42].

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 Transcranial magnetic stimulation López-Ibor et al. 643

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